Treatment of ocular disease

ABSTRACT

A formulation to treat ocular disease such as dry eye disease, as well as other diseases, is disclosed. Tacrolimus is administered either topically or by injection. For topical administration, an amount of about 1 ng to 10 μg may be formulated in an aqueous based cream that may be applied at bedtime or throughout the day. For injection, a dose of about 20-1000 μg/ml is used. Tacrolimus may also be administered in milligram quantities as a surgical implant contained in a diffusible walled reservoir sutured to the wall of the sclera, or may be contained within an inert carrier such as microspheres or liposomes to provide a slow-release drug delivery system.

FIELD OF THE INVENTION

The invention is directed to therapeutic treatment of ocular diseasessuch as dry eye disease.

BACKGROUND

Dry eye disease encompasses any condition where the tear film loseswater and becomes more concentrated. It is a common complaint, affectingthree million people in the United States alone, yet it is difficult todiagnose and treat. The loss of water from the tear film causes acorresponding rise in tear osmolarity. The increased osmolarity resultsin symptoms such as a sandy-gritty feeling in the eye, burning,irritation, or a foreign-body sensation that worsens during the day.Patients suffering from dry eye disease complain of mild to severesymptoms, with signs ranging from minimal superficial punctate keratitisto corneal perforation.

Dry eye disease has a chronic remitting and relapsing nature and mayresult from a number of factors. The disease may be a natural part ofthe aging process, affecting 15%-20% of adults over age 40. It may alsoresult from pathological processes such as diseases of the lacrimalglands, mucus glands, and/or lipid producing glands, and may occur withcell infiltration or atrophy of the lacrimal gland (Sjogren's Syndrome).Estrogen deficiency in postmenopausal women is also postulated to resultin dry eye disease.

One method to treat dry eye disease is by topical administration ofover-the-counter drugs that serve as artificial tears. Numerousvarieties of these artificial tears are available (TheraTears® (AdvancedVision Research), Refresh® and Celluvisc® (Allergan), Tears Natural® andBion Tears® (Alcon), GenTeal® and HypoTears® (CIBA Vision), each ofwhich contain electrolytes and has varying pH levels, osmolarities, andsurface tensions. Another method to treat dry eye disease is by surgeryto close the lacrimal drainage ducts using punctum plugs. Neithermethod, however, is completely desirable. Artificial tears do not have aconstant flow rate as do human tears, and treat the symptoms rather thecause of the disease. Surgery has its attendant risks, and may not be aviable option in older patients.

It is known that Cyclosporin A (cyclosporine, Allergan Inc.), may treatdry eye disease since patients administered cyclosporine for otherdisorders have shown a marked increase in tear flow. A topicalformulation containing Cyclosporin A (Arrestase®, Allergan Inc.) iscurrently under review by the Food and Drug Administration. CyclosporinA is an immunomodulator, suggesting that immune-mediated inflammationcontributes to dry eye disease. Cyclosporin A has been used to treatvarious ocular pathologies such as glaucoma, corticosteroid-inducedocular hypertension, allograft rejection, infections, and ocular surfacedisease. It is also known that Cyclosporin A may be used in the eye totreat uveitis (inflammation of the uvea) by topical, intravitreal orsystemic administration. Doses of 0.05%, 0.1%, and 0.5% cyclosporinehave been reported. Cyclosporin A has good penetration into the corneabut not into the anterior chamber, and does not increase intraocularpressure or cause cataracts.

Tacrolimus (Prograf®, previously known as FK-506) is an immunomodulatingdrug that has been applied topically to treat a variety of dermatoses.Topical administration of tacrolimus at doses ranging from 0.03%-0.3%resulted in significant clinical improvement in atopic dermatitis after2-3 weeks treatment, and tacrolimus treatment of other dermatologicdiseases shows promise. Tacrolimus, like cyclosporine, blocks the signaltransduction pathway needed to induce interleukin-2 gene expression andthereby activate T lymphocytes. In addition to suppressing T cellactivation, tacrolimus inhibits anti-lgE-triggered histamine release andinhibits prostaglandin D2 synthesis in human skin mast cells. While oraladministration produces limiting adverse effects (systemicimmunosuppression, infection, neural toxicity, nephrotoxicity, andhypertension), topical administration for treatment of dermatoses atconcentrations up to 0.3% showed no significant difference in effectsbetween treated and control groups. In addition, tacrolimus is welltolerated locally and only occasionally causes mild irritation.

The non-systemic use of tacrolimus in the treatment of ocular diseasesincluding dry eye disease would be advantageous.

SUMMARY OF THE INVENTION

The invention is directed to a method of treating ocular disease, suchas dry eye disease, uveitis, scleritis, neuritis, and/or papilitis, byproviding an effective amount of tacrolimus in a pharmaceuticallyacceptable formulation to a diseased eye. In one embodiment, theformulation is applied topically. In an alternative embodiment, theformulation is injected intraocularly, for example by subconjuctival,intravitreal, or retrobulbar injection. For subconjunctival injection aconcentration in the range of about 1 ng/ml to 500 μg/ml tacrolimus maybe used. For intravitreal injection a concentration in the range of1-1000 μg/0.1 ml may be used, with a preferred concentration of about 50μg/0.1 ml tacrolimus. For retrobulbar injection, a concentration in therange of about 20-1000 μg/ml tacrolimus may be used. Tacrolimus may beadministered in an aqueous-based solution, for example tacrolimus boundto liposomes, or tacrolimus dissolved in an organic solvent. Tacrolimusmay also be provided in an inert physiologically acceptable carrier bysurgical implantation, injection, or topical application.

The invention is also directed to a composition for treating dry eyedisease. The composition contains an effective amount of tacrolimus in apharmaceutically acceptable formulation. The formulation may be anaqueous cream or liquid containing, for example, about 1 ng to 10 μgtacrolimus. The formulation may be an inert carrier such as amicrosphere, liposome or polymeric matrix containing tacrolimus.Tacrolimus may be dissolved in an aqueous solvent such as 0.9% saline or5% dextrose, or an organic solvent such as dimethylsulfoxide (DMSO) oran alcohol.

The invention is additionally directed to a composition for intraocularinjection to treat ocular disease. An effective amount of tacrolimus isdissolved in either an aqueous solvent such as 0.9% saline or 5%dextrose, or an organic solvent such as DMSO or alcohol.

DETAILED DESCRIPTION

The invention is directed to a method and composition to treat oculardiseases by administration of tacrolimus (Prograf®, previously known asFK506). Tacrolimus, a macrolide immunosuppressant produced byStreptomyces tsukubaensis, is a tricyclo hydrophobic compound that ispractically insoluble in water, but is freely soluble in ethanol and isvery soluble in methanol and chloroform. It is available underprescription as either capsules for oral administration or as a sterilesolution for intravenous administration. The solution contains theequivalent of 5 mg anhydrous tacrolimus in 1 ml of polyoxyl 60hydrogenated castor oil (HCO-60), 200 mg, and dehydrated alcohol (USP,80.0%^(v/v)), and must be diluted with a solution of 0.9% NaCl or 5%dextrose before use.

Tacrolimus may be administered in a topical formulation for treatment ofocular disease. In one embodiment, tacrolimus in amounts ranging from 1ng to 10 μg is contained in an aqueous-based cream excipient. The drugmay be incorporated directly into the cream in the same solution as usedfor intravenous administration, or may be contained in liposomes ormicrospheres either in solution or in an anhydrous form. The creamformulation is usually applied to the eye at bedtime, but it may beapplied any time throughout the day if the cream does not cause blurredvision. Tacrolimus may also be applied topically in the form of eyedrops using the same solution for intravenous administration.

Tacrolimus may also be injected intraocularly, using intravitreal,subconjunctival, or retrobulbar injection. For subconjuctival injection,a dose in the range of 1 ng to 500 μg/ml may be used. For intravitrealinjection, a dose in the range of 1-1000 μg/0.1 ml my be used, with apreferred dose of 50 μg/0.1 ml. For retrobulbar injection, a dose in therange of 20-1000 μg/ml may be used. The intravenous solution form oftacrolimus may be diluted to achieve the indicated concentration using0.9% NaCl or 5% dextrose, or an organic solvent such asdimethylsulfoxide (DMSO) or alcohol, preferably a low molecular weightalcohol.

Tacrolimus may also be administered surgically as an ocular implant. Asone example, a reservoir container having a diffusible wall of polyvinylalcohol or polyvinyl acetate and containing milligram quantities oftacrolimus may be implanted in the sclera. As another example,tacrolimus in milligram quantities may be incorporated into a polymericmatrix having dimensions of about 2 mm by 4 mm, and made of a polymersuch as polycaprolactone, poly(glycolic) acid, poly(lactic) acid, or apolyanhydride, or a lipid such as sebacic acid, and may be implanted onthe sclera or in the eye. This is usually accomplished with the patientreceiving either a topical or local anesthetic and using a small (3-4 mmincision) made behind the cornea. The matrix, containing tacrolimus, isthen inserted through the incision and sutured to the sclera using 9-0nylon.

Tacrolimus may also be contained within an inert matrix for eithertopical application or injection into the eye. As one example of aninert matrix, liposomes may be prepared from dipalmitoylphosphatidylcholine (DPPC), preferably prepared from eggphosphatidylcholine (PC) since this lipid has a low heat transition.Liposomes are made using standard procedures as known to one skilled inthe art. Tacrolimus in amounts ranging from nanogram to microgramquantities is added to a solution of egg PC, and the lipophilic drugbinds to the liposome.

Tacrolimus bound with liposomes may be applied topically, either in theform of drops or as an aqueous based cream, or may be injectedintraocularly. In a formulation for topical application, the drug isslowly released over time as the liposome capsule degrades due to wearand tear from the eye surface. In a formulation for intraocularinjection, the liposome capsule degrades due to cellular digestion. Bothof these formulations provide advantages of a slow release drug deliverysystem, allowing the patient a constant exposure to the drug over time.

As another example, tacrolimus may be dissolved in an organic solventsuch as DMSO or alcohol as previously described and containing apolyanhydride, poly(glycolic) acid, poly(lactic) acid, orpolycaprolactone polymer.

Tacrolimus may also be used to treat other conditions of the eyeincluding uveitis (inflammation of the uvea), scleritis, (inflammationof the sclera), neuritis (inflammation of the optic nerve), or papilitis(inflammation of the optic nerve head) using the methods andformulations previously described. To treat uveitis, tacrolimus ispreferably injected subconjuctivally at a dose in the range of 1 ng/mlto 50 μg/ml, or intravitreally at a dose of about 1-1000 μg/0.1 ml,preferably about 50 μg/0.1 ml. To treat scleritis involving the anteriorsclera, tacrolimus is preferably administered topically. To treatscleritis involving the posterior sclera, tacrolimus is preferablyadministered by retrobulbar injection at a dose in the range of about20-1000 μg/ml and dissolved in DMSO or a low concentration of alcohol.To treat neuritis or papilitis, tacrolimus is preferably administered byretrobulbar injection at a dose in the range of about 20-1000 μg/ml.

It should be understood that the embodiments of the present inventionshown and described in the specification are only preferred embodimentsof the inventor who is skilled in the art and are not limiting in anyway. Therefore, various changes, modifications or alterations to theseembodiments may be made or resorted to without departing from the spiritof the invention and the scope of the following claims.

What is claimed is:
 1. A method of treating ocular disease comprisingproviding to a diseased eye a pharmaceutically acceptable formulationconsisting essentially of an effective amount of tacrolimus for treatinga disease selected from the group consisting of dry eye disease,scleritis, neuritis, papillitis, and combinations thereof.
 2. The methodof claim 1 wherein said formulation is applied topically.
 3. The methodof claim 1 wherein said formulation is injected intraocularly.
 4. Themethod of claim 3 wherein said formulation is injected subconjuctivally.5. The method of claim 4 wherein said formulation contains about 1 ng/mlto 500 μg/ml tacrolimus.
 6. The method of claim 3 wherein saidformulation is injected intravitreally.
 7. The method of claim 6 whereinsaid formulation contains about 1-1000 μg/0.1 ml tacrolimus.
 8. Themethod of claim 3 wherein said formulation is injected retrobulbarly. 9.The method of claim 8 wherein said formulation contains about 20-1000μg/ml tacrolimus.
 10. The method of claim 3 wherein said formulationcomprises tacrolimus in an aqueous-based solution.
 11. The method ofclaim 10 wherein said aqueous-based solution contains tacrolimus boundto liposomes.
 12. The method of claim 3 wherein said formulationcomprises tacrolimus in an organic solvent.
 13. The method of claim 3wherein said formulation comprises liposomes with anhydrous tacrolimus.14. The method of claim 1 wherein said formulation comprises tacrolimuscontained in an inert carrier.
 15. The method of claim 14 wherein saidcarrier containing tacrolimus is provided to said diseased eye by amethod selected from the group consisting of surgical implantation,injection, and topical administration.
 16. A method for treating oculardisease consisting of an intraocular injection of an effective amount oftacrolimus dissolved in a solvent selected from the group consistingessentially of an aqueous solvent and an organic solvent for injectinginto an eye to treat a disease selected from the group consisting of dryeye disease, scleritis, neuritis, papillitis, and combinations thereof.17. The method of claim 16 containing about 1 ng/ml to 1000 μg/mltacrolimus.
 18. The method of claim 16 wherein said aqueous solvent isselected from the group consisting of 0.9% NaCl and 5% dextrose.
 19. Themethod of claim 16 wherein said organic solvent is selected from thegroup consisting of dimethylsulfoxide and alcohol.